However, from post to follow-up, psychopathological symptoms decreased more in the control group than in the intervention group, so that only the intervention effects for PROMIS-depression (β = -0.10) and PROMIS-anger (β = -0.09) remained until follow-up. Moreover, positive affect (β = 0.19), internal control beliefs (β = 0.15), favorable coping (β = 0.60), and unfavorable coping (β = -0.41) improved more in the intervention group than in the control group, and these effects were mostly maintained in the long term. Some effects were stronger among women, older individuals, and individuals with higher initial symptoms. These findings suggest that AR can effectively reduce mental health problems in daily life.Applied Relaxation (AR) is an established behavioral mental health intervention, but its efficacy in real life contexts remains unclear. Using randomized controlled trial data, we examined whether AR can effectively reduce mental health problems in daily life. A sample of 277 adults with increased psychopathological symptoms but without 12-month DSM-5 mental disorders at study entry was randomly assigned to an intervention group receiving AR training (n = 139) and an assessment-only control group (n = 138). Ecological momentary assessments were used to assess psychological outcomes in daily life over a period of seven days at baseline, post, and 12-month follow-up, respectively. Multilevel analyses indicated that all psychopathological symptoms decreased more in the intervention group than in the control group from baseline to post . Mental disorders are common and rank among the top causes and risks for years lived with disability around the world. They relate not only to individual impairments but also to tremendous societal costs –7. An imCognitive-behavioral models suggest that psychophysiological tension plays an important role in a cascade of symptoms that reinforce each other and can result in full-threshold mental disorders over time ,9. RelaxA well-known relaxation technique is Applied Relaxation (AR). Originally developed to treat anxiety disorders, it is conceptualized as a behavioral coping technique that enables individuals to rapidly relax within 20 to 30 seconds as soon as the first signs of tension or stress appear . AR can As single treatment or part of a multimodal program, AR has been shown to effectively reduce depressive, anxiety, stress, or somatic symptoms in the context of various mental disorders and physical diseases. For instance, AR reduced anxiety symptoms in patients with generalized anxiety disorder –16, paniA randomized controlled trial recently investigated whether AR lowers existing psychopathological symptoms and thus prospectively prevents the onset of subthreshold and full-threshold mental disorders in the following months ,46. PartThe conventional questionnaires at the respective main assessment revealed that the primary  and secondary  outcomes of the intervention efficacy improved more in the intervention group than in the control group from baseline to post. However, these group effects did not persist until follow-up. That is, AR led to accelerated improvements in various psychopathological symptoms. In addition, a reduction of incident (sub)threshold mental disorders as primary outcome of the prevention efficacy was observed.The current analysis addresses secondary research questions from this RCT . The aimFinally, we aim to examine whether the intervention efficacy varies by sex, age, and initial symptom severity at baseline. Investigating such moderator effects is crucial for specifying high-risk groups that might particularly benefit from AR training. According to theories of motivation  and healThe current study does not overlap with previous work  because A randomized controlled parallel-group superiority trial with an intervention group and an assessment-only control group was conducted from 9/2016 to 11/2019 at the Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Germany . ParticiThe trial included a baseline, post, and 12-month follow-up assessment. The post assessment was conducted directly after the intervention in the intervention group and after a comparable time frame  in the control group. The follow-up assessment was conducted approximately 12 months after the post assessment. Conditions were not blinded.The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees for experiments on humans and the Helsinki Declaration of 1975 as amended in 2013. The study was approved by the ethics committee of the Technische Universität Dresden (EK508112015). All participants gave written informed consent after being completely informed about the study. They received an expense allowance of 8.50 euros per hour for their participation in the post and follow-up assessment, respectively.Participants were recruited via flyers, advertisement, and media articles from the general population and cooperating institutions in the Dresden area. Individuals interested in the study were screened for initial inclusion criteria (see below) via a secured webpage hosted by the Technische Universität Dresden. Individuals who met these criteria were invited to a face-to-face entry exam, during which a standardized diagnostic interview modified for DSM-5 (DIA-X-5)  was condInclusion criteria were at least mild depressive, anxiety, or stress symptoms   and an aThe AR intervention was manualized following the procedures of Öst ,52 and cN = 4) had a psychology study background and were trained in AR by the principal investigators (KBB and/or EA) and supervised throughout the study. The AR course manual and materials are available upon request from KBB or EA.The course sessions were accompanied by weekly homework . In addition, participations were instructed to document daily stressful episodes and associated psychophysical, cognitive, behavioral, and/or emotional symptoms in a tension/stress diary . Homework assignments were prepared and discussed in each course session. All course instructors , cognitive , and behavioral  outcomes were assessed via EMA. That is, participants were given a smartphone and instructed to answer a battery of items in time to experience five times a day for one week. Individual assessments were scheduled based on a time sampling scheme with variable assessment intervals. To keep the EMA short and feasible, individual scales were slightly abbreviated. Some items were slightly reworded so that they referred to the time interval after the last assessment . Items were answered with a slider-response ranging from 0 to 100. Items are available upon request from KBB or EA.In the evening, depressive, anxiety, and stress symptoms on the respective day were assessed with the DASS-21 , which wDepressive, anxiety, anger, and somatic symptoms as well as sleep disturbances since the last assessment were assessed with the DSM-5 Level 2 Cross-Cutting Symptom Measures ,54). MorAt each wave, positive affect since the last assessment was assessed with the respective subscale of the Positive and Negative Affect Schedule (PANAS) , labeledIn the evening, internal and external control beliefs on the respective day were assessed with the 4-item Internal External Control Scale (IE-4)  and selfIn the evening, participants were also asked whether anyone or anything had bothered, upset, or disturbed them on that particular day. If participants affirmed this question, favorable  and unfavorable  coping strategies in that situation(s) were measured with individual subscales of the Stress Coping Questionnaire , labeledIn this trial, changes in depressive, anxiety, and stress symptoms (assessed with the DASS-21 at the respective main assessment) in the intervention vs. control group from baseline to post were defined as the primary outcome of the intervention efficacy. Rates of incident mental disorders in the intervention vs. control group from entry exam to follow-up were defined as the primary outcome of the prevention efficacy. Findings for these outcome measures have been previously presented .Secondary outcomes of the intervention efficacy included changes in other symptom measures  and clinical changes  in the intervention vs. control group from baseline to post. Secondary outcomes of the prevention efficacy included changes in depressive, anxiety, stress, and other symptoms as well as clinical changes in the intervention vs. control group from post to 12-month follow-up. No important changes to the methods or trial outcomes were made after trial commencement.As previously presented , we assuAnalyses were performed using Stata 15 . MultileTo test whether intervention effects varied by (a) sex, (b) age, and (c) levels of the respective outcome at baseline, a three-way interaction term was included from the timing variable, the group variable, and (a) sex, (b) age, or (c) levels of the considered outcome at baseline, respectively. The variable “sex” was coded as 0 in men and 1 in women.M = 0, SD = 1) based on the pooled standard deviation of the intervention and control group at baseline. The age variable (in years) was divided by 10 to ensure that the effects did not become too small to be presented rounded. All analyses were adjusted for sex and age. The alpha level was set at .05. The Benjamini-Hochberg procedure was used to reduce the false discovery rate and correct for multiple testing [Because some symptoms were left-skewed and their residuals were not normally distributed, all outcomes were log-transformed (log(x+1)). To enable comparisons between different outcome measures and groups, all log-transformed outcomes were further standardized across all waves  participated at baseline, 229 individuals  participated at post, and 225 individuals  participated at follow-up. The sample included 87 men and 190 women aged 18–55 years at baseline . In the intervention group, 105 of 139 participants (75.5%) completed AR training with M = 7.82 sessions attended (range 4 to 10). Only 18 (13.0%) did not attend any course session, and 16 (11.5%) terminated the training early after attending M = 3.25 sessions (range 1 to 6). More detailed information, including a CONSORT flow chart as well as sociodemographic and clinical characteristics of the sample, has been published elsewhere [A total of 277 individuals  provided EMA data at baseline, 225 individuals  provided EMA data at post, and 142 individuals  provided EMA data at follow-up. A total of 277 subjects answered the EMA at baseline and/or post, 233 at post and/or follow-up, and 275 at baseline and/or follow-up. Thus, the analyses on changes from baseline to post, from post to follow-up, and from baseline to follow-up are based on 277, 233, and 275 individuals, respectively. The numbers of individuals and observations for individual outcomes at baseline, post, and follow-up are shown in Of the total sample, 275 individuals (intervention group: p < .001). Chi-squared tests showed that missing values for individual outcomes did not vary by sex or group . The only exception was that information on PROMIS-depression and positive affect was missing more often in the control group than in the intervention group, and that information on favorable and unfavorable coping as well as positive affect was missing more often in men than in women.As indicated by little’s MCAR test, the data were not completely missing at random (β = 0.13), DASS-stress scores (β = 0.15), PHQ-15-somatic symptoms (β = 0.31), and PROMIS-sleep problems (β = 0.18) but lower PROMIS-depression scores (β = -0.10). In addition, women reported lower positive affect (β = -0.05) but higher internal control beliefs (β = 0.14) as well as more favorable (β = 0.21) and more unfavorable (β = 0.38) coping.Sex and age differences in baseline outcome measures are shown in β = 0.03 per decade), PHQ-15-somatic symptoms (β = 0.11), and PROMIS-sleep problems (β = 0.09) but lower PROMIS-depression scores (β = -0.04). In addition, older individuals reported lower internal (β = -0.07) and higher external (β = 0.08) control beliefs, higher self-efficacy (β = 0.05), and less unfavorable coping (β = -0.15).Compared with younger individuals, older individuals had higher PROMIS-anger scores  and PROMIS-anger (β = -0.09) were maintained from baseline to follow-up.Means and standard deviations for individual outcomes at baseline, post, and follow-up in the intervention and control group are shown in β = 0.19), cognitive , and behavioral  outcomes improved more in the intervention group than in the control group, except for external control beliefs and self-efficacy. The effects from baseline to follow-up were similar. In addition, self-efficacy increased more in the intervention than in the control group from baseline to follow-up (β = 0.19).Intervention effects for other psychological outcomes are shown in M = 0.15, SD = 0.50; control: M = 0.16, SD = 0.49; t(8120) = 1.01, p = .312). At post, the intervention group  attempted to consciously relax more often than the control group  = -32.47, p < .001). Although the number of relaxations attempts in the intervention group decreased from post to follow-up, this group difference was still significant at follow-up  = -15.96, p < .001).At each EMA, participants were asked to indicate how many times they had consciously attempted to relax since the last assessment.  The number of relaxation attempts did not differ between the two groups at baseline (intervention: β = -0.16) and PHQ-15-somatic symptoms (β = -0.39) were stronger in women than in men (β = -0.26) and PHQ-15-somatic symptoms (β = -0.27) were stronger in women than in men.From baseline to post, the intervention effects for PROMIS-depression (time*group*sex: n in men . From baβ = 0.22), self-efficacy (β = 0.35), and favorable coping (β = 0.79) were stronger in women, whereas the intervention effect for unfavorable coping was stronger in men , whereas the intervention effect for favorable coping was stronger in women (β = 0.96).From baseline to post, the intervention effects for positive affect  was higher in men.β = -0.27 to β = -0.08 per 10 years older).Especially in the long term, AR tended to be more effective in older individuals : The intβ = 0.20 per 10 years older), whereas the intervention efficacy for favorable coping was stronger in younger individuals (β = -0.45 per 10 years older).Fewer interactions with age were found for other psychological outcomes : From baβ = -0.34 for PROMIS-depression to β = -0.16 for DASS-depression). However, the intervention effect for PROMIS-sleep was stronger among participants with fewer sleep problems at baseline (β = 0.25).As shown in β = -0.17), DASS-stress (β = -0.26), PROMIS-depression (β = -0.12), and PROMIS-anxiety (β = -0.20) were also stronger among individuals with higher initial levels of the respective symptoms. Conversely, the intervention effects for DASS-anxiety (β = -0.17) and PROMIS-anger (β = -0.17) from baseline to follow-up were stronger among individuals with lower initial levels of the respective symptoms.From baseline to follow-up, the intervention effects for DASS-total (β = -0.24) and from baseline to follow-up (β = -0.42) was stronger among individuals with lower internal control beliefs at baseline.Regarding other psychological outcomes , the intThis analysis of randomized controlled indicated prevention trial data in adults with elevated psychopathological symptoms but without full-threshold mental disorders at study entry examined whether group-based AR training effectively reduced psychopathological symptoms in real-life contexts, assessed in time to experience via smartphone-based EMA. Results illustrate that AR training led to significant improvements in all psychopathological symptoms examined and in health-related emotional, cognitive, and behavioral characteristics. A large proportion of these improvements were not only observed from baseline to post but persisted through 12-month follow-up.Compared with the control group, the intervention group experienced greater decreases in several psychopathological symptoms from baseline to post, including depressive, anxiety, stress, anger, and somatic symptoms as well as sleep problems. Moreover, the intervention group improved more in terms of positive affect, perceived control, and coping behaviors due to AR training. A large proportion of these effects was maintained over the long term and still seen after one year. These results are consistent with our hypotheses and with previous evidence that AR was effective in reducing psychopathological symptoms , particularly in patient samples –25. FurtThe present findings not only replicate but substantially extend previous evidence on AR: Most prior studies focused on small samples, patients with full-threshold mental disorders, or single outcomes assessed with conventional questionnaires. In contrast, our study was based on a comparatively large sample of high-risk individuals with elevated psychopathological symptoms but without full-threshold mental disorders at study entry. Various internalizing and externalizing symptoms and other health-related psychological outcomes were assessed using established scales. To minimize retrospective memory and reporting biases and evaluate the efficacy in real-life contexts, diagnostic information was collected via smartphone-based EMA in time to experience five times daily for one week at each wave. Taken together, our findings suggest that AR training promotes successful transfer to everyday life, indicating that AR can be used effectively to manage daily stressful situations.For several outcomes, AR tended to be more effective in individuals with higher baseline symptoms. This result is consistent with our hypotheses based on motivational theories ,48: IndiAR tended to be more effective in women than in men, particularly with respect to internalizing outcomes such as anxiety and somatic symptoms. These results are in line with our hypotheses and with meta-analytic findings that relaxation training reduces anxiety more effectively in women . HoweverIt was found that AR tended to be more effective in older individuals. This result is inconsistent with our hypotheses and with meta-analytic evidence that relaxation training was less effective in older individuals . Older iOur study is not without limitations: Only short scales were used in the EMA, which may be less reliable than other, more comprehensive questionnaires. Diagnostic information was collected via self-report, which may differ from clinical expert ratings or behavioral observations.There was no active control condition, so it was not possible to test whether AR or unspecific factors such as treatment expectations and regular contact with psychological trainers led to symptom improvements. However, compared with the control group, participants in the intervention group were more likely to consciously relax in daily life at post and follow-up, suggesting that the intervention led to behavioral changes that explain the intervention efficacy.Only one follow-up was conducted at 12 months, so nuanced symptom changes in the months after the intervention could not be examined. Additional follow-ups are also needed to evaluate the long-term efficacy after more than one year.The study was based on a convenient sample of adults aged between 18 and 55 and living in the Dresden area. Therefore, the present results may not be fully generalizable to other age and regional groups. Moreover, more women (68.6%) than men participated in the study, and many individuals (48.7%) did not provide EMA data at 12-month follow-up. At the same time, the intervention efficacy tended to be higher in women and individuals with more severe baseline symptoms, and more burdened individuals might have been more likely to skip the EMA at follow-up. Thus, one could speculate whether the intervention effects might have been overestimated. In this study, participants were given a smartphone to answer the EMA. In future studies, it may be useful to enable participants to conduct the EMA on their own smartphone to reduce the risk of dropout.Our study suggests that group-based AR training significantly reduces psychopathological symptoms in daily life and leads to improvements in health-related emotional, cognitive, and behavioral traits. These favorable effects of AR training tend to be stronger in women than in men, in older than in younger individuals, and in participants with higher vs. lower baseline symptoms.Our findings underscore the importance of promoting transfer from the training setting to everyday life in prevention and early intervention programs. Future research may investigate (a) which contextual and situational factors increase or decrease the efficacy of AR in everyday life and (b) how to improve the long-term efficacy of AR training. In the intervention group, the number of relaxation attempts decreased from post to follow-up, highlighting the importance of additional booster sessions . In this context, mobile technologies could be useful to remind participants regularly to use AR in stressful daily situations. Furthermore, the effectiveness in everyday life could be tested among particularly stressed groups such as health professionals, shift workers, or single parents.S1 Checklist(DOC)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 Table(DOCX)Click here for additional data file.S7 Table(DOCX)Click here for additional data file.


First-line chemotherapy for patients with metastatic pancreatic cancer (MPC) includes gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX (FFX). However, the efficacy of second-line chemotherapy and the role of combination chemotherapy in clinical practice is still unknown. Data was gathered from 14 hospitals in the Kyushu area of Japan from December 2013 to March 2017. The median overall survival (mOS) from second-line treatment was contrasted between patients who received second-line chemotherapy (CT group) and those who received the best supportive care (BSC group). Furthermore, the mOS of combination chemotherapy was compared to mono chemotherapy in the CT group. To control possible bias in the selection of treatment, we performed a propensity score-adjusted analysis. A total of 255 patients received GnP or FFX as first-line chemotherapy. There were 156 in the CT group and 77 in the BSC group of these. The CT group had a significantly longer mOS than the BSC group  0.38; 95% CI 0.27–0.54). In the CT group, 89 patients received combination chemotherapy while 67 received mono chemotherapy. The mOS did not differ significantly between the combination and mono chemotherapy groups . Among patients with MPC receiving second-line treatment, the CT group had a significantly longer mOS than the BSC group, but combination chemotherapy conferred no improvement in survival compared to mono chemotherapy. Pancreatic cancer is estimated to cause 40,000 new diagnoses and 33,000 deaths in Japan each year2. This disease is an outlier in the overall trend of decreasing cancer-related mortality. The five-year overall survival rate for locally advanced pancreatic cancer was 6.1%, while it was only 1.3% for metastatic disease3. For the past two decades, gemcitabine-based chemotherapies have been the standard of care for patients with advanced and metastatic pancreatic cancer5. Furthermore, two active combination regimens, FOLFIRINOX  (FFX) and gemcitabine plus nab-paclitaxel (GnP), have garnered acceptance as first-line treatment8Pancreatic cancer has a poor prognosis and is having an increasing impact on cancer-related mortality in Japan and globally11. In clinical practice, the regimen used for first-line therapy, as well as the patient’s Eastern Cooperative Oncology Group performance status (ECOG-PS) and organ function, influence the choice of second-line treatment. Active combination regimens are recommended by the ASCO clinical practice guidelines for patients with an ECOG-PS of 0 or 1 and a favorable comorbidity profile12. However, until the recent approval of nanoliposomal irinotecan , significant data to support the use of combination regimens in a second-line setting were insufficient.Although these active regimens are available following the failure of first-line therapy, there is little evidence of their efficacy in second-line treatment. Despite the unmet medical need for evidence-based second-line therapies, only a few pivotal phase III trials have been performedWe evaluated the efficiency of second-line treatment after FFX or GnP first-line chemotherapy for metastatic pancreatic cancer (MPC). First, the efficacy of second-line chemotherapy was contrasted with best supportive care (BSC). Second, patient survival was contrasted following second-line mono chemotherapy or combination chemotherapy.From December 2013 to March 2017, 102 and 153 patients with MPC initially received FFX and GnP, respectively. 156 of these patients received second-line chemotherapy, while 77 received BSC. In the second-line group, 89 patients received combination chemotherapy  and 67 patients received monochemotherapy   .According to a provisional analysis of the fundamental dataset, the median overall survival (mOS) (second-line) for the chemotherapy group was 5.2 months and 2.7 months for the BSC group  The mOS from the first-line was 11.5 months for the chemotherapy group and 7.8 months for the BSC group . The logistic regression model’s c-statistics value for calculating the propensity score was 0.75 (95% CI 0.68–0.82).In the propensity score-adjusted analysis, mOS (after second-line treatment) was 5.2 months for the chemotherapy group and 2.6 months for the BSC group . In the IPTW analysis, the mOS after second-line treatment for the chemotherapy group was 5.5 months and 2.5 months for the BSC group .Following propensity score-matching, 98 chemotherapy group patients were matched with 61 BSC group patients (Table P = 0.49)  .Table 49) Fig. a. A prel48) Fig. b. After P = 0.92). The mOS (after second-line treatment) was 5.5 months for the combination chemotherapy group and 4.8 months for the mono chemotherapy group . After first-line treatment, the mOS after first-line treatment was 12.3 months for the combination chemotherapy group and 11.1 months for the mono chemotherapy group . The logistic regression model’s c-statistics value for calculating the propensity score was 0.82 (95% CI 0.76–0.89).In the propensity score-adjusted analysis, the mPFS (after second-line treatment) was 2.6 months for the mono chemotherapy group and 3.0 months for the combination chemotherapy group . The mOS from the second-line was 6.4 months for the combination chemotherapy group and 6.5 months for the mono chemotherapy group . In IPTW analysis, the mOS from the second-line was 5.5 months for the combination chemotherapy group and 3.8 months for the mono chemotherapy group .After propensity score-matching, 35 patients in the combination chemotherapy group were matched with 35 patients in the mono chemotherapy group Table . The mPFThe survival period of patients with MPC remains very short because this disease is resistant to chemotherapy and progresses rapidly. The sequencing of therapeutic options in the second-line setting for patients with MPC remains a significant unfulfilled need. We examined the outcomes of second-line treatment using the cohort of patients who received FFX or GnP as a first-line therapy. First, we conducted a study that focused on comparing survival with chemotherapy versus BSC. Second, we compared survival following second-line combination chemotherapy or mono chemotherapy.9. Although this study ended prematurely due to low enrollment, the OFF regimen was associated with significantly higher survival after second-line treatment compared with BSC .Most prior randomized control trials (RCT) did not compare active treatment with BSC. The first and only phase III RCT compared BSC to oxaliplatin, fluoropyrimidine (5-FU), and folic acid (FA) (OFF regimen) in 46 patientsP < 0.01). However, because these two groups may differ in terms of background factors after first-line treatment failure, a propensity score-adjustment analysis was performed before second-line treatment by selecting clinically meaningful variables. The adjusted results also revealed a statistically significant increase in mOS for patients receiving second-line chemotherapy versus those that chose the second-line BSC group , P < 0.01). These findings suggest that administering any second-line chemotherapy to patients who are considered chemotherapy tolerant will help to prolong survival.In our study, 77 patients received BSC after FFX and GnP failed. There is no data comparing chemotherapy to BSC in the second-line treatment setting after refractory response to intensive chemotherapy regimens such as FFX and GnP. Survival of the second-line chemotherapy group was considerably longer than the BSC’s , P = 0.04). In contrast, no differences in the frequency of neutropenia, febrile neutropenia, or gastrointestinal toxicity were observed between the groups, all of which had no impact on the transition to second-line treatment or BSC. Reports have shown that anemia is associated with chemotherapy resistance, with our study showing a similar trend13. For cases with grade 3 or higher anemia, depending on the situation after first-line treatment failure, BSC may be considered as a necessary option. In Analysis 2, no differences in adverse events occurring during first-line treatment were observed between the combination and monotherapy groups. For patients who exhibited severe peripheral neuropathy during first-line treatment, avoiding regimens that may cause peripheral neuropathy during second-line treatment may not decrease their QOL.As a criterion for selecting a regimen for second-line treatment, we confirmed the correlation between the adverse events that occurred during first-line treatment Table . AnalysiPatient background data for Analysis 1 showed that the BSC group had a higher proportion of patients with a history of resection than did the chemotherapy group. We believe that there are two reasons for such a finding. The first reason for this is that in Japan, S-1, a fluoropyrimidine-based agent, is the standard of care for adjuvant chemotherapy, whereas gemcitabine-based regimens are selected for recurrence. When this regimen becomes ineffective, treatment options are limited and BSC may be considered. The second reason is that this study used a database from a period wherein the safety of FFX in second-line therapy was not well established. Therefore, FFX may have been less commonly selected among patients refractory to gemcitabine-based regimen.The validity of second-line therapy for recurrent cases after surgery remains controversial. However, given that it is being carried out in clinical practice, we conducted an adjusted analysis. Regarding the validity of chemotherapy for postoperative cases, we are currently conducting a prospective investigation on the matter (NAPOLEON2 study).14. However, the possibility that mPC and rPC contribute to prognosis cannot be ruled out in second-line treatment; hence, additional prognostic analyses were conducted. Notably, Analysis 1 showed no significant difference between the two groups, with mPC (n = 196) and rPC (n = 37) at 4.0 and 4.9 months, respectively . Similarly, Analysis 2 showed no significant difference between the two groups, with mPC (n = 137) and rPC (n = 19) at 5.1 and 8.9 months, respectively . In both Analysis 1 and Analysis 2, no significant differences were observed between the two groups.In recurrent or advanced pancreatic cancer, the prognostic difference based on the background cannot be ignored. In a sub-analysis of the main study, survival data for metastatic PC (mPC) and recurrent (rPC) treated with FFX or GnP therapy as first-line treatment were analyzed, with our findings showing that rPC had a favorable prognosis. However, propensity score-matched analysis revealed no difference in prognosis between the two groups with chemotherapyp = 0.01, median time to progression 2.9 versus 2.0 months, p = 0.019)10. On the other hand, FOLFOX has been observed to be subordinate to 5-FU/FA for OS , but no difference was observed in PFS 15; thus, leaving the significance of oxaliplatin in second-line therapy unclear. The NAPOLI-1 study, a pivotal phase III RCT, found that nal-IRI plus 5-FU/FA significantly improved survival compared with 5-FU/FA  and PFS  in patients previously treated with a gemcitabine-based regimen11. The mOS and mPFS in various phase III RCTs of second-line pancreatic cancer treatment is inconsistent, ranging from about 3.3 to 9.9 months and 1.5 to 3.1 months15. Most studies to date have evaluated second-line regimens following gemcitabine-based therapy failure. Furthermore, there is little evidence supporting the choice between combination chemotherapy or mono chemotherapy for patients who are refractory to FFX or GnP treatment.Although nal-IRI and 5-FU/FA combination therapy is recommended for second-line treatment after a gemcitabine-based regimen fails, data regarding the efficacy of other combination regimens are lacking. A few pivotal phase III trials have been conducted. In a phase III RCT, the OFF regimen significantly improved survival in patients with gemcitabine refractory pancreatic cancer compared with a 5-FU/FA regimen; the benefit of additional oxaliplatin was also demonstrated  or PFS  as compared to the mono chemotherapy group. Propensity score-adjustment analysis did exert significant differences in OS  or PFS . After the end of the second-line treatment, there were 85 evaluable patients in the combination chemotherapy group and 60 patients in the mono-chemotherapy group, respectively. Of these patients, 30 (35%) were in the combination chemotherapy group and 14 (23%) were in the mono-chemotherapy group. There was no significant difference between the two groups in terms of third-line chemotherapy transition (p = 0.12); however the clinical impact was undeniable  as compared to mono chemotherapy (S-1); the results are currently awaited (UMIN000043939).Conclusively, after comparing chemotherapy versus BSC, if the patient’s tolerability is tolerable, second-line chemotherapy for patients with MPC can be expected to prolong survival. Regarding the treatment options, combination chemotherapy does not always contribute to longer survival and that mono chemotherapy should also be considered a viable option.This study was conducted as a multicenter retrospective study of patients with unresectable or recurrent pancreatic cancer who received GnP and FFX first-line chemotherapy (NAPOLEON study) by medical oncology and gastroenterology specialists practicing in Japan’s Kyushu region. The institutional review board of each participating institution authorized the NAPOLEON study. We reviewed the medical records of consecutive patients with unresectable or recurrent pancreatic cancer who began FFX or GnP as first-line chemotherapy from December 2013 to March 2017. We excluded patients with locally advanced diseases in this study.As the regimens of the second-line chemotherapy aside GnP and gemcitabine plus S-1, FFX included original and modified FOLFIRINOX, gemcitabine plus Erlotinib, fluorouracil/ l-leucovorin plus oxaliplatin, gemcitabine, and S-1 were included in the analysis. Patients who received other second-line treatments  were excluded. Patients receiving two or more drug regimens were categorized as the combination chemotherapy group, while patients treated with a single drug regimen, gemcitabine or S-1, were classified as the mono chemotherapy group. The induction dose for the second-line chemotherapy was left to the physicians’ discretion.The primary goal of the study was overall survival (OS). Secondary endpoints included progression-free survival (PFS). OS was calculated from the administration date of second-line chemotherapy to the date of death from any cause or censored at the final follow-up examination. BSC was thought to begin after the first sign of disease progression following treatment first-line chemotherapy. PFS was calculated from the date of second-line chemotherapy administration to the date of progression or death from any cause, whichever occurred first or was censored at the final follow-up examination.Χ2-test was used. OS and PFS were estimated using the Kaplan–Meier method and comparisons of the probability of survival were conducted using the log-rank test and the Cox proportional hazards model. The hazard ratio (HR) was represented with a 95% confidence interval (95% CI). Differences with P < 0.05 values were considered substantial. We used propensity score-adjusted analyses to control for potential selection bias linked with nonrandomization. The propensity score was calculated using the logistic regression model using the following covariates: age, ECOG-PS, duration of first-line chemotherapy, resection of the primary lesion, first-line regimen, reason for first-line chemotherapy withdrawal for second-line chemotherapy, performance versus BSC  and first-line regimen, age, ECOG-PS for combination chemotherapy versus mono chemotherapy . The covariates were selected based on the pretreatment background characteristics of the primary dataset, which were utilized by clinicians when deciding on treatment. We also refer to the suggested baseline variables, according to the international consensus statement used to examine the efficacy and safety of systemic therapy for unresectable pancreatic cancer18. A propensity score-matched analysis and inverse probability of treatment weighting (IPTW) were used to establish sensitivity to evaluate the associations between treatment selection and endpoints. The logistic regression model’s predictive accuracy was evaluated using c-statistics. The Cox proportional hazard model was applied to the fundamental dataset with propensity scores and treatment groups as covariates, and a propensity score-adjusted analysis was performed. Propensity score-matched analysis utilized a two-to-one for analysis 1 and a one-to-one for analysis 2 nearest-neighbor matching with the caliper set to 0.2. Statistical analyses were conducted using R ver. 3.5.3 .We initially performed preliminary analyses of the original cohort  to estimate the effects of treatment. For continuous data, the Mann–Whitney test was used, and for categorical data, the This study was conducted in accordance with the ethical guideline of the Declaration of Helsinki and was centrally approved by the Institutional review board of Saga Medical Center Koseikan (study ID 17-09-01-02), and also approved by the Institutional Review Boards or Ethics Committee of following institutions: Imari Arita Kyoritsu Hospital, Japanese Red Cross Kumamoto Hospital, Kagoshima City Hospital, Oita University Hospital, Kagoshima University Hospital, Kurume University Hospital, Japan Community Healthcare Organization Kyushu Hospital, Saiseikai Sendai Hospital, Nagasaki University Hospital, Hamanomachi Hospital, Sasebo Kyosai Hospital, Karatsu Red Cross Hospital and Fukuoka Wajiro Hospital prior to the study. Because this study was a retrospective observational study carried out in Japan, informed consent was obtained using the opt-in/opt-out approach according to each participating institution’s policy.Supplementary Table 1.


Treating patients for metastatic prostate cancer based on the information of PSMA-PET bears the risk to “under- or overtreat” patients, given that many lesions seen only on PSMA-PET but not on conventional imaging (CI) could alter their management. It is not possible to predict the disease status using CI with PSMA-PET/CT, because bone lesions can be positive on bone scintigraphy (BS), without evidence of the disease on CT. Some authors suggested using clinical parameters to predict BS results, but this does not reach enough accuracy to adjust the therapy. If an algorithm based on PSMA-PET/CT data were able to predict if lesions are visible on BS, this might be a possible way to adjust patient management based on CI-based guidelines in light of PSMA-PET/CT. Therefore, we aimed to develop a model to predict the visibility of bone lesions on BS based on PSMA-PET/CT data.max, SUVmean, PSMAtot, PSMAvol, density, diameter on CT, and presence of cortical erosion were collected. Clinical variables  were also considered. Two experienced double-board physicians decided whether a bone metastasis was visible on the BS, with a consensus readout for discordant findings. For predictive performance, a random forest was fit on all available predictors, and its accuracy was assessed using 10-fold cross-validation performed 10 times. Results: A total of 43 patients were identified with 222 bone lesions on PSMA-PET/CT. A total of 129 (58.1%) lesions were visible on the BS. In the univariate analysis, all PSMA-PET/CT parameters were significantly associated with the visibility on the BS (p < 0.001). The random forest reached a mean accuracy of 77.6% in a 10-fold cross-validation. Conclusions: These preliminary results indicate that there might be a way to predict the BS results based on PSMA-PET/CT, potentially improving the comparability between both examinations and supporting decisions for therapy selection.Objective: The increasing use of PSMA-PET/CT for restaging prostate cancer (PCa) leads to a patient shift from a non-metastatic situation based on conventional imaging (CI) to a metastatic situation. Since established therapeutic pathways have been designed according to CI, it is unclear how this should be translated to the PSMA-PET/CT results. This study aimed to investigate whether PSMA-PET/CT and clinical parameters could predict the visibility of PSMA-positive lesions on a bone scan (BS). Methods: In four different centers, all PCa patients with BS and PSMA-PET/CT within 6 months without any change in therapy or significant disease progression were retrospectively selected. Up to 10 non-confluent clear bone metastases were selected per PSMA-PET/CT and SUV The significantly higher accuracy of prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) over conventional imaging (CI), consisting of a bone scan (BS) and a contrast-enhanced CT, for prostate cancer (PCa) was proven in a prospective randomized trial , increasFurthermore, innovative therapeutic approaches for PCa are emerging such as targeted radiotherapy (RT) for oligometastatic disease and also in patients after progression to androgen deprivation therapy (ADT) . This opUnfortunately, it is not possible to compare the CI-based disease status with PSMA PET/CT. Indeed, nodal or visceral diseases seen on PSMA PET/CT can be projected to the theoretical results of CT, given that the anatomic size of a lesion is assessable using both techniques. On the other hand, bone lesions can be positive on the BS without evidence on the CT component and vice versa . NumerouIn this retrospective multicentric study (n = 4), we screened all PCa patients who between 1 September 2016 and 31 March 2022 underwent a PSMA PET/CT showing at least one suspicious bone lesion and a BS followed/preceded within 6 months (n = 97). Then, we included only patients without any change in therapy between both scans (n = 44), to exclude any morphologic or metabolic changes due to therapy. Finally, we excluded one case for a clear progression between the 2 scans n = 43, . The stu68Ga]Ga-PSMA-11 PET/CT scans 60 ± 10 min after the administration of a median dose of 148.6 MBq (77–370), while 26 patients underwent [18F]PSMA-1007 PET/CT ninety minutes after the administration of a median dose of 319.5 MBq (210–375). Furthermore, a whole-body BS was performed 180 min after the administration of a mean dose of 717.6 ± 82.1 MBq of [99mTc]Tc-HDP in 36/43 patients and of 664.9 ± 42.7 MBq of [99mTc]Tc-DPD in 7/43 patients. All institutional protocols agreed with the joint EANM-SNMMI procedure guidelines Ga-PSMA-11 PET/CT and BS.In max, SUVmean, PSMAtot, PSMAvol, maximum uptake diameter, maximum lesion diameter at CT, HU) and the clinical variables  between the positive and negative lesion visible on thet BS were assessed with t-tests. Chi-square tests of independence were used for the assessment of dependence between the lesion visibility on the BS and the presence of cortical erosions, the applied tracer, the lesion location, and the ISUP grade. To evaluate the interrater agreement on BS assessment, Cohen’s kappa test was used. Values < 0.2, 0.21–0.39, 0.4–0.59, 0.6–0.79, 0.8–0.9, and >0.9 were considered of none, minimal, weak, moderate, strong, and almost perfect agreement/reliability, respectively [Descriptive analyses were used to display patient data as means with standard deviations or medians with ranges to describe normally or non-normally distributed values, respectively; a frequency distribution with percentages was used to summarize categorical variables. Univariate differences in the means of the imaging variables  was fit to all 8 imaging variables and the 6 abovementioned clinical variables as fixed effects, and random intercepts were used for the patient identifier and the study center. The model was fit with the package lme4 . Then, bFor the prediction study, a random forest was fit to all 8 imaging and 6 clinical variables. A 10-fold cross-validation was performed 10 times. The reported accuracy of lesion visibility represents the mean of all runs and all folds. The patient identifier and the study center were not used in the prediction study. For the comparisons of the random forest model with a simple binary regression using only the visibility on CT (lesion’s CT diameter > 0 cm) as a predictor, receiver operator characteristics (ROC) were built and the area under the ROC-curve (AUROC) was calculated and compared with Delong’s test.p-value of less than 0.05 was considered statistically significant. Statistical analyses were performed with R [A d with R  and SPSSWe identified forty-three patients  who underwent PSMA PET/CT and a BS within a mean of 55 ± 49.3 days. Most of the patients were scanned for CRPCa (74.5%). The initial mean ISUP grade was four. The main patient characteristics are given in On PSMA PET/CT scans, 222 lesions were selected. The lesions were distributed as follows: ribs 42/222 (19%), spine 69/222 (31%), pelvis 44/222 (20%), extremities 50/222 (22.5%), sternum 7/222 (3%), and skull 10/222 (4.5%).max (1.8–95) as well as PSMAvol (0–103 cm3). For lesions with SUVmax < 4, the PSMA volume parameters were considered = 0 cm3 (n = 11). CT diameter was non-measurable and set to 0 cm for 53 lesions without any morphologic correlate on CT (considered invisible on CT); of these, 19 (35%) lesions were positive on the BS.There was a wide range of PSMA activity for SUVOn the other hand, measurable lesions on CT with clear sclerosis  were negative on the BS in 14/39 (36%). Lesion characteristics are given in In total, 129 of 222 (58%) PSMA-positive skeletal lesions were visible also on the BS, according to the consensus read out. The inter-rater agreement between the two double-board radiologists and nuclear medicine physicians was moderate with k = 0.653.max, SUVmean, PSMAvol, PSMAtot, and max diameter on PET (uptake) and CT were significantly higher in visible (129/222) compared to non-visible BS lesions (93/129) (p < 0.001) as shown in max from PSMA PET. In addition, the lesion density on CT (HU) was significantly higher in BS-positive lesions compared to negative ones (p = 0.018). The slight difference in terms of the presence of cortical erosion between the two groups did not reach significance (p = 0.064); no significant difference between groups was also observed for PSA (p = 0.46) and ISUP values  of 244.4. The final model had a pseudo marginal R2 of 0.38 and a pseudo conditional R2 of 0.54.The variable importance of the mixed-effects logistic regression fit to the 8 PSMA PET/CT parameters and 6 clinical variables  and random intercepts for the patient identifier and the study center were analyzed by a backwards elimination procedure. This procedure stopped with the variables SUVp < 0.001, A random forest was fit to the 8 imaging and 6 clinical variables. In the 10-times repeated 10-fold cross-validation, the random forest classifier attained a mean accuracy over all the runs and folds of 77.6%. The corresponding AUROC of the random forest was 0.82, which was significantly higher compared to the AUROC of a simple binary regression with only CT-visibility as a predictor .Despite a very heterogeneous cohort and a relatively long-time interval between BS and PSMA PET/CT in the current data set, the random forest model with 10-fold cross-validation yielded an accuracy of 77.6% to predict the visibility of PSMA-positive bone lesions on the BS. This is superior compared to a model that always assumes visibility on the BS . The accuracy was also significantly higher for the random forest model based on PET/CT parameters compared to a simple model incorporating visibility on CT alone  of bone lesions did not remain significant. This might be explained by the fact that visibility on CT alone does not give a good answer if a lesion is present on the BS or not, given that 35% of the lesions negative on CT were positive on the BS, while 36% of measurable lesions on CT were negative on the BS. Therefore, the proposed complex model incorporating PET and CT data yielded better results compared to the simple “visibility on CT” to predict a visible lesion on the BS  can be  lesions , even if1007 and 8GaGa-PSM lesions . SimilarBone scans are not commonly used for staging anymore, but still play a pivotal role in the response assessment given that PSMA PET/CT is not an approved modality for this yet and is recommended to be used only within clinical trials . These tAn inherent limitation of studies assessing bone metastasis is the lack of a histopathological gold standard. Ethical considerations regarding additional pain and inherent difficulties in performing PET/CT-guided biopsies would not justify a large enough cohort with biopsy-proven metastasis. Therefore, we decided to strictly focus on image comparability, regardless of the nature of the lesion. Furthermore, the moderate kappa for the read out of the BS between two expert readers is limiting as well. The insecure labeling of the gold standard limits the potential of every model, which is a general problem for predictions of subjective parameters such as lesion visibility. Finally, in our population, we have to point out the presence of a certain heterogeneity in terms of the main ongoing therapy which may hamper PSMA expression .These preliminary results indicate that there might be a way to predict BS results based on PSMA PET/CT. This could improve the comparability between both examinations and help to interpret PSMA PET/CT results in the light of the CI-based guidelines for accurate therapy selection in patients with metastatic PCa in the future. The currently achieved accuracy is insufficient for reliable predictions, but it might be improved in larger cohorts or with the integration of further features that need more standardization .


A three-dimensional window screen (3D-Screen) has been developed to create a window double-screen trap (3D-WDST), effectively capturing and preventing the escape of mosquitoes. A 2015 laboratory study demonstrated the 3D-Screen's efficacy, capturing 92% of mosquitoes in a double-screen setup during wind tunnel assays. To further evaluate its effectiveness, phase II experimental hut trials were conducted in Muheza, Tanzania.Three experimental hut trials were carried out between 2016 and 2017. Trial I tested two versions of the 3D-WDST in huts with open or closed eaves, with one version using a single 3D-Screen and the other using two 3D-Screens. Trial II examined the 3D-WDST with two 3D-Screens in huts with or without baffles, while Trial III compared handmade and machine-made 3D structures. Mosquito capturing efficacy of the 3D-WDST was measured by comparing the number of mosquitoes collected in the test hut to a control hut with standard exit traps.Trial I showed that the 3D-WDST with two 3D-Screens used in huts with open eaves achieved the highest mosquito-capturing efficacy. This treatment captured 33.11% (CI 7.40–58.81) of female anophelines relative to the total collected in this hut (3D-WDST and room collections) and 27.27% (CI 4.23–50.31) of female anophelines relative to the total collected in the control hut . In Trial II, the two 3D-Screens version of the 3D-WDST captured 70.32% (CI 56.87–83.77) and 51.07% (CI 21.72–80.41) of female anophelines in huts with and without baffles, respectively. Compared to the control hut, the capturing efficacy for female anophelines was 138.6% (37.23–239.9) and 42.41% (14.77–70.05) for huts with and without baffles, respectively. Trial III demonstrated similar performance between hand- and machine-made 3D structures.The 3D-WDST proved effective in capturing malaria vectors under semi-field experimental hut conditions. Using 3D-Screens on both sides of the window openings was more effective than using a single-sided 3D-Screen. Additionally, both hand- and machine-made 3D structures exhibited equally effective performance, supporting the production of durable cones on an industrial scale for future large-scale studies evaluating the 3D-WDST at the community level. Plasmodium parasites and transmitted to humans through the bite of female Anopheles mosquito [Anopheles gambiae s.s. (sensu stricto), An. funestus s.s. [An. stephensi are endophagic (feeds indoor) in nature, vectors like An. arabensis from the same species complex (An. gambiae sensu lato) as An. gambiae s.s. exhibit both endophagic and exophagic (feeds outdoor) behavior [An. gambiae s.s. and An. funestus s.s. mostly exhibit endophilic behavior where they spend a considerable amount of time indoors post blood meal; however, some studies have reported exophilic behavior as well [Anopheles arabensis, on the other hand, exhibits exophilly [Malaria is a vector-borne infection caused by mosquito . It is emosquito , 2. The tus s.s. , 4, and behavior , 6. Simi as well . Anophelxophilly , 9 with xophilly , 11. ExoITNs and IRS are major vector control approaches currently under the WHO recommended guidelines and are included in most large-scale malaria vector control campaigns. Although the use of long-lasting ITNs was a great achievement in minimizing human-mosquito contact whereby regular mosquito nets are subjected to insecticide treatment and the emission takes place slowly during the lifespan of a net, the extensive use of malaria control measures, based on insecticides, has resulted in the emergence of insecticide-resistant mosquitoes , 13, whiIn a laboratory phase study , we deve2 , Trial II (May–June 2017), and Trial III (November–December 2017), during which two versions of the 3D-WDST setup, a 3D-WDST made of a 3D-Screen and a traditional screen or two 3D-Screens (the tips of the cones were facing the inner space of the 3D-WDST) and two versions of the cone material , were evaluated. The huts with fitted 3D-WDST were assigned as treatment huts, and the mosquito-capturing performance of the 3D-WDST was estimated and compared to a control hut. The control hut was fitted with the standard exit traps  on all w016, Triai.SO–The 3D-WDST was made of a 3D-Screen facing the outside and a traditional screen facing the inside of the hut and the eaves were open.ii.SC–The 3D-WDST was made of a 3D-Screen facing the outside and traditional screen facing the inside of the hut and the eaves were closed.iii.DO–The 3D-WDST was made of two 3D-Screens on both sides of the double-screen setup and the eaves were open.iv.DC–The 3D-WDST was made of two 3D-Screens on both sides of the double-screen setup and the eaves were closed.v.C–The control hut was with exit traps on all four sides, north and south verandas and the eaves were open.The trial ran for 30 nights, and the following evaluation arms were studied:i.Topen–The 3D-WDST was made of two 3D-Screens on both sides of the double-screen setup and the eaves were open.ii.Tbaffles–The 3D-WDST was made of two 3D-Screens on both sides of the double-screen setup and the eaves had baffles.iii.Copen–The control hut was with exit traps on all four sides and all the verandas, and the eaves were open.iv.Cbaffles–The control hut was with exit traps on all four sides, the north and south verandas were screened, and the eaves had baffles.The trial ran for 36 nights, and the following evaluation arms were studied:Topen and Tbaffles were run in duplicates. Data analyses were performed from the average outcomes of each replicate of Topen and Tbaffles.Six huts were used for the trial, and the treatments i.open–The cones of the 3D-Screens were made of traditional screen material, the 3D-WDST was made of two 3D-Screens on both sides of the double-screen setup, and the eaves were open.HMii.baffles–The cones of the 3D-Screens were made of traditional screen material, the 3D-WDST was made of two 3D-Screens on both sides of the double-screen setup, and the eaves had baffles.HMiii.open–The cones of the 3D-Screens were manufactured from plastic, the 3D-WDST was made of two 3D-Screens on both sides of the double-screen setup, and the eaves were open.MMiv.baffles–The cones of the 3D-Screens were manufactured from plastic, the 3D-WDST was made of two 3D-Screens on both sides of the double-screen setup, and the eaves had baffles.MMv.Cbaffles–The control hut was with exit traps on all four sides, north and south verandas were screened, and the eaves had baffles.vi.Copen–The control hut had exit traps on all four sides, all verandas and the eaves were open.The trial ran for 36 nights, and the following evaluation arms were studied:Two volunteers were recruited for each hut to sleep under untreated bed nets every test night from 1900 to 0630 h. Sleepers were alternated between the experimental huts on successive nights to remove possible bias due to differences in individual attractiveness to mosquitoes, and treatments were rotated weekly on the experimental huts to adjust for any differences in positional attractiveness of the huts using a Latin square design Fig. A. SundayMosquitoes were collected by a team of trained field entomologists every morning (except Sundays) from the 3D-WDSTs, the exit traps (control huts), and verandas (control huts). The 3D-Screens were affixed to the window frames using Velcro tapes. Mosquitoes trapped in the 3D-WDSTs were collected by inserting a hand-held mouth aspirator through a small opening created by temporarily detaching the Velcro tape Fig. B. Hand-hg for 5 min, and the supernatant was transferred to a fresh 96-well plate. DNA extraction was conducted using the Kingfisher Flex Magnetic Particle Processor (ThermoFisher scientific) following manufacturer’s instructions. Quality control for the extracted DNA was performed using Quant-iT™ PicoGreen™ assay kit (ThermoFisher Scientific). DNA was finally stored in 96-well plates at − 20 °C for further molecular analyses.Genomic DNA was extracted from whole-body samples of all female anopheline mosquitoes collected throughout the study. Mosquito specimens were transferred into 2-ml screw cap tubes containing 250 mg zirconia powder and six 3-mm silica glass beads, and a repeating bead-beating (RBB) was performed at 1400 rpm for 60 s . To the resulting homogenate, 200 µl lysis buffer  was added, and RBB was performed three times with incubation at room temperature for 5 min after each step. Final homogenate was centrifuged at 9000An. gambiae s.l. morphologically in the laboratory were further identified to the sibling species using polymeric chain reaction (PCR) method described previously [Anopheles mosquitoes with the malaria parasite, all mosquito DNA samples were subjected to P. falciparum infection analysis using nested PCR method as described by Snounou et al. [Species identified as eviously . To deteu et al. . PCR proThis study was conducted following the guidelines of the Declaration of Helsinki and the international guidelines for ethical review of epidemiological studies. Both verbal and written consents were taken from the volunteers (sleepers) after explaining the nature of the study. The risk of malaria was explained, and all volunteers were provided chemoprophylaxis during the trial period and 1 month post trial period. All volunteers were also monitored daily for fever and malaria symptoms. All procedures for data collection, management, storage, and analysis followed standard operating procedures. Ethical clearance was sought from the ethics committees of the National Institute of Medical Research (NIMR) Tanzania (Ref: NIMR/HQ/R.8a/Vol. IX/2399).TT) = sum of collection from the 3D-WDSTs from east, west, north, and south wing.Total collection from 3D-WDST (TET) = sum of collection from the exit traps from the control huts from east, west, north, and south wing.Total collection from exit traps (TRT) = total collection from room obtained after 30 man-min of manual catching using a mosquito aspirator.Catches from room, treatment hut, (TRC) = total collection from room obtained after 30 man-min of manual catching using a mosquito aspirator.Catches from room, control hut, (TTR) = TT + TRTTotal collection in treatment huts (TC) = (2 × Verandas) + TET + TRCTotal collection in control huts  the following day. Mosquito specimens were recorded as the number of daily catches and species from traps, rooms, and verandas. Mosquito recording was further summarized, adjusted, and represented as follows.The total numbers of mosquitoes in the two veranda traps from the control hut were multiplied by two to adjust for the unrecorded escapes through the other two verandas which were left unscreened to allow routes for entry of mosquitoes via the eaves , 26.Two alternative methods were used to calculate the efficacy of the 3D-WDST in capturing mosquitoes entering the treatment huts. The first calculated the capturing efficacy percentage relative to the total number of mosquitoes collected from both the 3D-WDSTs and the room of the respective treatment. On the other hand, the second calculated the capturing efficacy percentage relative to the total number of mosquitoes collected from both the exit traps and the room of the control hut.Excel data were further summarized and converted into pivot tables to summarize the collection in different setup regarding species, collection hut, and gonotrophic statuses of specimen.t test was used when comparing two groups, and one-way analysis of variance (ANOVA) followed by post hoc Tukey’s multiple pairwise comparisons or Fisher's least significant difference (LSD) test was used when comparing more than two groups. A probability value of P < 0.05 was indicative of statistical significance in all tests. All calculations were performed using the GraphPad Prism 9 software package . Descriptive statistics and statistical analyses to establish difference between treatment arms and plots generation were also conducted using GraphPad Prism.Data are presented as means and standard deviations (SD). Shapiro-Wilk test for normality was performed. For data sets returning normal distribution, In Trial I, we investigated whether a 3D-WDST with a single 3D-Screen (SO and SC treatments) or with two 3D-Screens (DO and DC treatments) would perform better in capturing mosquitoes under semi-field conditions. In the same experimental setup, we also investigated whether closing the eaves of the huts (SC and DC treatments) or leaving them open (SO and DO treatments) would affect the mosquito-capturing capacity of the 3D-WDST. Results of these comparisons, including the average weekly (5 days) mosquito counts, statistical parameters, and significant differences are summarized in Table n = 211 and 71.94% female, n = 541) and 244 as culicines . Further morphological identification of anophelines identified 433 mosquito specimens as An. gambiae s.l.  and 319 specimens as An. funestus s.l. . Female anophelines were sorted and analyzed for P. falciparum infection analysis. Female anophelines morphologically identified as An. gambiae s.l. were subjected to PCR assay for sibling species identification (n = 303). From the molecular analyses, 288 were An. gambiae s.s. and 15 were An. arabensis. Additionally, 37 specimens were found to be infected with P. falciparum, 15 were An. gambiae s.s., and 22 were An. funestus s.l., while none were An. arabiensis. In the 3D-WDST of the DO hut condition, 1/48 and 1/28 captured An. gambiae s.s. and An. funestus s.l. were P. falciparum positive, respectively. In the 3D-WDST of the SO hut condition, 0/6 and 1/2 captured An. gambiae s.s. and An. funestus s.l. were P. falciparum positive, respectively. The other two treatment conditions, DC and SC, had no P. falciparum-infected mosquitoes in the 3D-WDST.A total of 996 mosquitoes were collected during the collection period of 30 nights of which 752 were morphologically identified as anophelines  between the weekly mean female anopheline mosquito counts inside the 3D-WDST of at least one pair of the four treatments. Tukey's multiple comparison test was carried out for all possible pairs of treatments (6 pairs). There was strong evidence  of a significant difference between DO treatment and DC, SC, and SO treatment  while the other two had baffles (Tbaffles) fixed in the eaves. Two more huts served as controls (one with open eaves and the other with baffles), and the trial ran for 6 weeks with weekly rotation of huts and daily rotation of sleepers.Trial I demonstrated that 3D-WDST fitted to windows of experimental huts with open eaves captured significantly more mosquitoes than those fitted to huts with closed eaves. This suggests that a significant number of mosquitoes entered the huts through the eaves and got captured in the 3D-WDST while leaving the hut space in the early morning. Still another route for mosquitoes leaving the hut space in the morning is the eaves themselves. Therefore, we asked what would the 3D-WDST capturing efficacy be if we permitted mosquito entry through the eaves and block mosquito escape through them using baffles? To answer this question, Trial II was conducted in which four huts were fitted with 3D-WDST; two of them had open eaves  mean mosquito counts, statistical parameters, and significant differences, are summarized in Table n = 339 and 64.16% female, n = 607) and 783 were culicines . Anophelines consisted of 42.50% An. gambiae s.l.  and 47.50% An. funestus s.l. . Of 365 female anophelines morphologically identified as An. gambiae s.l. that were subjected to PCR assays for sibling species identification, 360 were An. gambiae s.s. and 5 were An. arabensis. In addition, PCR assay for P. falciparum detection was performed on all female anophelines (n = 607) of which P. falciparum infection was found in 28 An. gambiae s.s. and 14 in An. funestus s.l. while none were found in An. arabiensis. In the 3D-WDST of the Topen hut condition, 8/97 and 1/24 captured An. gambiae s.s. and An. funestus s.l. were P. falciparum positive, respectively. In the 3D-WDST of the Tbaffles hut condition, 5/73 and 2/62 captured An. gambiae s.s. and An. funestus s.l. were P. falciparum positive, respectively.A total of 1729 mosquitoes were collected during the collection period of 36 nights of which 946 were anophelines  between the weekly mean female anopheline mosquito counts inside the 3D-WDST of Topen and Tbaffles. The weekly mean female anopheline mosquito count in the 3D-WDST of Topen was 10.08 (CI 2.4–17.76) and in the 3D-WDST of Tbaffles was 11.25 (CI 3.40–19.09). The mosquito capturing efficacy relative to the total number of female anopheline mosquitoes collected in the respective treatment hut was 51.07% (CI 21.72–80.41) and 70.32% (CI 56.87–83.77) for Topen and Tbaffles, respectively. The mosquito-capturing efficacy relative to the total number of female anopheline mosquitoes collected in the respective control hut was 42.41% (CI 14.77–70.05) and 135.1% (CI 42.88–227.3) for Topen and Tbaffles, respectively. The capturing efficacy of 3D-WDST in hut conditions Topen and Tbaffles is summarized in Table The Tbaffles compared with the Topen, although the difference was not statistically significant (P = 0.06), Fig. Topen was 8.67 (2.22–15.11) and in the 3D-WDST of Tbaffles was 18.08 (CI 8.57–27.59).Interestingly, using baffles led to an increase in the number of female culicine mosquitoes in the 3D-WDST of the baffles and MMbaffles) were also included in the experimental design in addition to the open eave huts (HMopen and MMopen) to replicate Trial II in the context of a different rainy season since Trial I and II were conducted in May–June 2016 and 2017 (long rainy season), respectively, while Trial III was conducted in November–December 2017 (short rainy season).In Trial III, we tested two production methods for the cone structures used to produce the 3D-Screens of the 3D-WDST. The cones that were used in Trial I and II were made of screen mesh material of the same type used to hold the cones and produce the setup of the 3D-WDST. These cones were handmade (HM), although laser was used to cut the mesh into the desired shapes. To improve integrity, reproducibility, and manufacturability of the cones, they were also produced in a factory using the injection molding manufacturing process . In Trial III, HM and MM cones were used to produce the 3D-Screen for the 3D-WDST setup. HM- and MM-based 3D-WDST were then tested under experimental hut conditions to compare their efficacy in mosquito capturing. Experimental huts with the baffle system (HMAn. gambiae s.l. and 1905 were An. funestus s.l.) and 156 were culicines. Since a significant proportion of anophelines were morphologically characterized as An. funestus s.l. (98.65%), we did not perform PCR assays for sibling species identification; however, a subset of daily female anophelines  collected from each treatment regarding their collection wing were randomly selected for Plasmodium infection analysis. Of 772 mosquitoes selected for PCR assay, 22 were infected, and all infected specimens were An. funestus s.l. In the 3D-WDST of the MMopen and MMbaffles conditions, 1/54 and 1/58 tested An. funestus s.l. specimens  were P. falciparum positive, respectively. The other two treatment conditions, HMopen and HMbaffles, had no P. falciparum-infected mosquitoes in the 3D-WDST.Data of the different hut conditions, including the weekly 6 days) mean mosquito counts, statistical parameters, and significant differences, are summarized in Table  days meaopen was 10 (2.70–17.3) and in the 3D-WDST of MMopen was 16.83 (2.62–31.04). Although there were more mosquitoes in the 3D-WDST of the MMopen condition than in the HMopen condition, 16.83 vs. 10, respectively, the uncorrected Fisher's LSD test did not show a significant difference (P = 0.1887) between the weekly mean female anopheline mosquito counts inside the 3D-WDST of the two conditions. However, these data suggest that the cones made by injection molding, i.e. the MM cones, showed a similar or even better performance to that of the cones made of screen mesh, i.e. the HM cones. These findings warrant production of durable cones at industrial scale for future large-scale studies to evaluate 3D-WDST at community levels. Further analyses of the data showed that the mosquito-capturing efficacy relative to the total number of female anopheline mosquitoes collected in the respective treatment hut was 24.44% (8.06–40.82) and 30.55% (9.386–51.71) for HMopen and MMopen, respectively. The mosquito capturing efficacy relative to the total number of female anopheline mosquitoes collected in the respective control hut was 30.44% (− 1.142 -62.02) and 27.8% (14.86–40.75) for HMopen and MMopen, respectively. These efficacy data suggest that 3D-WDST built with HM or MM cones had similar efficacies. Using baffles in the huts had no significant effect on the weekly mean female anopheline mosquito counts in the 3D-WDST of the HMopen vs. HMbaffles or the MMopen vs. MMbaffles  and 3.16 (− 1.50 to 7.83), respectively. The capturing efficacy of 3D-WDST in different hut conditions is summarized in Table The data showed that the weekly mean female anopheline mosquito count in the 3D-WDST of HMwas 10 2.0–17.3 anAn. gambiae s.l. in the study area. In contrast, Trial III took place during the short rainy season in November–December 2017 when An. funestus s.l. was known to be more abundant than other malaria vector species.Meteorological conditions influence the relative abundance of various mosquito species by affecting the suitability and availability of breeding habitats. Trials I and II were conducted during the long rainy season in May–June of 2016 and 2017, respectively. This period was known for the prevalence of the malaria vector An. gambiae s.l. and An. funestus s.l. were captured in the 3D-WDST in approximately equal numbers in both trials  and industrially manufactured plastic cones. The results of the three semi-field trials that took place in 2 successive years and covered long and short rainy seasons showed that the 3D-WDST setup made of two 3D-Screens was effective in capturing up to 51% (24–51% depending on the year and the rainy season) of the mosquitoes entering and escaping the experimental huts through the windows.While window screening to control malaria is not new –33, the The trial results demonstrate a reasonable agreement with the laboratory study data, where the cone-based 3D-Screen prototype effectively captured a substantial percentage (92%) of the mosquitoes introduced into the wind tunnel when utilized in a double-screen configuration . HoweverTbaffles treatment condition) in the eaves, which act as a funneling system for mosquito entry while blocking their escape. Although the capturing efficacy was higher for the Tbaffles condition, the absolute count of the captured mosquitoes was similar in the 3D-WDST of the Topen and Tbaffles conditions, suggesting that the enhancement of the calculated efficacy was due to fewer free mosquitoes collected in the hut spaces of the Tbaffles condition possibly because of limited entry of mosquitoes through the baffles. This could indicate that blocking eaves as exit point had limited effect on the number of mosquitoes trapped in the 3D-WDST. On the other hand, the number of culicines was marginally higher, although statistically insignificant (P = 0.06), in the 3D-WDST of huts with baffles compared to those with open eaves. This could suggest that culicines tended to exit houses through eaves, and when eaves were blocked they tried to find other exit points such as window openings. It could also suggest that more culicines entered the huts through the eaves because of either their overall abundance or their persistence to enter the huts through the baffles, although the latter has to be proven in other studies. Based on these results, we decided to test an industrial design of 3D-Screens in the third trial and compared it with the design used in the first two trials. While the two versions of screens differed only in the material used, they performed equally in terms of their efficacy. The findings from the third trial allowed us to evaluate the design of the 3D-Screens for future large-scale implementation, which will require a cost-effective production process. The experimental hut studies did not assess the impact of environmental factors such as temperature, humidity, and rainfall on 3D-WDST. Additionally, the long-term integrity and durability of the 3D-WDST could not be assessed because of the limited duration of the studies. However, the 3D-Screens with industrially manufactured cones would likely be able to endure various field conditions because of the durable plastic materials used in the production of the cones.The installation of the 3D-WDST in huts with open eaves led to a higher number of trapped mosquitoes compared to huts with closed eaves. This could suggest that some mosquitoes entered the huts through the eaves at night, escaped through the 3D-WDST in the morning, and got trapped, while in huts with closed eaves mosquitoes that were captured in the 3D-WDST were those that entered the huts only through the 3D-WDST. This indicates that both eaves and windows were mosquito entry points and the 3D-WDST could be more effective in controlling mosquito population when entry points such as eaves are left open. Additionally, the 3D-WDST setup featuring two 3D-Screens was notably more effective than the 3D-WDST configuration with only one 3D-Screen. This improved performance can be credited to the design of the setup, which enables mosquitoe trapping from both the exterior and interior of the house. Following this finding, in Trial II we explored the efficacy of the 3D-WDST with two 3D-Screens, creating a scenario where mosquitoes could freely enter the huts through open eaves but could not escape through them, allowing only window openings as exit point. This was achieved by introducing baffles , the intervention will likely receive a greater community acceptance because it provides a permanent solution to stop mosquito entry through windows and reduces the mosquito population in the surroundings. A similar entry trap, Lehmann’s funnel trap, has been tested in the field condition and has demonstrated significant efficacy in capturing mosquitoes as well , 38. WhiCurrent practice for indoor mosquito management in Africa mostly relies on usage of LLINs and IRS. Most houses in the countryside are locally made using mud bricks and timbers available within the surroundings. House-proofing against mosquitoes by closing eaves and other ports of mosquito entry means compromising the ventilation, and the practice is less favored. Qualitative studies conducted earlier have also shown that different aspects of personal comfort play important roles in the decision to use nets regularly. Barriers to comfort such as feeling uncomfortable, suffocation, feeling captured inside, perceived difficulty in breathing, or feeling itchy also influence the daily net usage –42. The


Lungsco01 is the first study assessing the real benefits and the medico-economic impact of video-thoracoscopy versus open thoracotomy for non-small cell lung cancer in the French context.Two hundred and fifty nine adult patients from 10 French centres were randomised in this prospective multicentre randomised controlled trial, between July 29, 2016, and November 24, 2020. Survival from surgical intervention to day 30 and later was compared with the log-rank test. Total quality-adjusted-life-years (QALYs) were calculated using the EQ-5D-3L®. For medico-economic analyses at 30 days and at 3 months after surgery, resources consumed were valorised (€ 2018) from a hospital perspective. First, since mortality was infrequent and not different between the two arms, cost-minimisation analyses were performed considering only the cost differential. Second, based on complete cases on QALYs, cost-utility analyses were performed taking into account cost and QALY differential. Acceptability curves and the 95% confidence intervals for the incremental ratios were then obtained using the non-parametric bootstrap method . Sensitivity analyses were performed using multiple imputations with the chained equation method.vs. €11,290 ) and at 3 months  vs. €11,912 ). In the cost-utility analyses, the incremental cost-utility ratio was €19,162 per additional QALY gained at 30 days . The acceptability curve revealed a 64% probability of efficiency at 30 days for video-thoracoscopy, at a widely-accepted willingness-to-pay threshold of €25,000 (34% at 3 months). Ratios increased after multiple imputations, implying a higher cost for video-thoracoscopy for an additional QALY gain .The average cumulative costs of thoracotomy were lower than those of video-thoracoscopy at 30 days  Given our results, the economic efficiency of video-thoracoscopy at 30 days remains fragile at a willingness-to-pay threshold of €25,000/QALY. The economic efficiency is not established beyond that time horizon. The acceptability curves given will allow decision-makers to judge the probability of efficiency of this technology at other willingness-to-pay thresholds.NCT02502318. Lung cancer (LC) remains a major health problem with an estimated 130,180 deaths in 2022 in the US, which makes it the leading cause of cancer death in both sexes –6. MoreoDuring the last decade, the use of video-assisted thoracoscopic surgery (VATS) lobectomy for LC has grown considerably. In France, the use of VATS jumped from 12% of lobectomies in 2012 to 48% in 2017  for VATS vs. 99.22% [95% CI: 94.58 – 99.89] for thoracotomy), or at 3 months after the surgery (81.21% [95% CI: 45.15 – 94.70] for VATS vs. 79.37% [95% CI: 41.27 – 94.15] for thoracotomy). There was no significant difference in the risk of death between the two groups. The difference in risk of death at 30 days was -0.035 after thoracotomy compared to after VATS . The difference in risk of death at 3 months was -0.004 after thoracotomy compared to after VATS . For 30-day mortality, the odds ratio was 0.5 (95% CI: 0.17 - 1.52). For 90-day mortality, the odds ratio was 0.94 (95% CI: 0.37–2.4).There was no significant difference in the baseline clinical characteristics between the two groups Table . InterveThe QALYs assessed at each point of administration were slightly higher for VATS compared to thoracotomy, but the difference was not significant Table .p-value = 0.003). There was a difference in average cumulative costs at 3 months of €2,049  between the groups, with a significantly higher costs in the VATS group than in the thoracotomy group . In both analyses, the costs attributed to VATS were higher than those of thoracotomy, mainly due to the cost of the initial stay . The detailed cost results are presented in Table There was a difference in average cumulative costs at 30 days of €1,560  between the groups, with significantly higher costs in the VATS group than in the thoracotomy group . There was a difference in the average number of final QALYs at 30 days of 0.068 (95% CI: 0.0036 to 0.1323), significantly in favour of the VATS group . This resulted in an ICER of €19,162 per additional QALY gained. The bootstrap analysis resulted in a mean ICER of €126,304 . A total of 97.61% of the bootstrapped cost-utility pairs were located in the northeast quadrant of the CU-plane, meaning higher costs and more QALYs following VATS  revealed an increase in the ICER  , after excluding in this order: (i) patients who died before the D30-visit; (ii) patients for whom the D-30 visit was performed much earlier or later than 30 days; (iii) patients with an undated D30-visit; (iv) patients with missing data for the EQ-5D-3L® . There was a difference in the average number of final QALYs of 0.0404 (95% CI: 0.0316 to 0.1123) in favour of the VATS group, but the effect was not significant . This resulted in an ICER of €36,733 per additional QALY gained. The bootstrap analysis resulted in a mean ICER of €324,310 . A total of 86.14% of the bootstrapped cost-utility pairs were located in the northeast quadrant of the CU-plane, meaning higher costs and more QALYs following VATS  revealed an increase in the ICER    and higher, but not significantly, QALYs at 3 months . As in our study, QALYs were assessed using EQ-5D-3L® and were imputed in case of missing data. However, they found lower overall costs per patient operated by VATS , and 84.3% of the bootstrapped cost-utility pairs were located in the bottom-right quadrant of the CU-plane, meaning lower costs and more QALYs following VATS. The probability of VATS being cost-effective was 95% at DKK 50,000/QALY  according the acceptability curve. However, there were some differences between our studies: theirs was monocentric, designed for the first 12 months following surgery, from the perspective of healthcare services, and included additional costs . Another more recent publication from 2021 comparing cost and effectiveness between VATS and open lobectomy in China concluded that hospitalization costs were similar for the two strategies, but that there were lower post-surgical costs and higher effectiveness for VATS [This trial is the first prospective multicentre RCT to assess the medico-economic impact of VATS compared with open thoracotomy for the management of NSCLC in France. To our knowledge, only one other cost-utility study by Bendixen et al. has been published to date comparing the two strategies . This Dafor VATS . Howeverfor VATS . In 17 ofor VATS .Major surgery on the thorax”) for which we had only to determine a level of severity , those for other re-hospitalisations had to be determined. Moreover, though the production costs per DRG are available in the ENCC, these remain average costs, calculated from 70 representative establishments in France, with the disadvantage of lacking precision on inter-individual variability [The present study has several limitations. Only the hospital perspective was considered insofar as only hospital resources consumed were available based on the data collected in the e-CRF. In this perspective, in order to calculate the production cost per stay as recommended in medico-economic guidelines , 30, theiability . Howeveriability . The caliability . Then, siability , the aveiability , 35. Theiability . Anotheriability .Haute Autorité de Santé (HAS) [DRG-adjusted approach for the initial stays and of combination of micro-costing and gross-costing approaches. While micro-costing identifies and measures the resources consumed by the innovative intervention, gross-costing estimates the cost items that can be valued using standard costs (ex: for readmissions related to complications). Finally, our study is one of the few studies that takes ‘utility’ into consideration, though it is a particularly important dimension for medico-economic studies in lung cancer [Nonetheless, this study has several strengths. This is the first multicentre RCT in France to prospectively evaluate the cost-utility impact of VATS versus open thoracotomy in the management of NSCLC, considering costs from the initial stay and patient follow-up (re-admissions), and utility (QALYs). The centres were required to have performed 50 VATS procedures to be included in the study, thus limiting biases linked to the experience of the surgeons performing VATS. The costing methodology used conforms to the methodological recommendations of health economists  and the té (HAS) , in termg cancer , 37–40.Pulmonary lobectomy, by thoracotomy, with preparation by thoracoscopy), whose valuation (838.75 €) is insufficient considering the real cost of VATS surgery . In our context, the revaluation of VATS should take into account the acceptability threshold of willingness-to-pay that will be set by decision-makers in terms of acceptable supplemental costs per additional QALY gained. Other additional criteria could also be taken into consideration, depending on the decision-making context. For example, multi-criteria decision analysis (MCDA) could also be relevant since it provides information on a wider range of outcomes including physical functioning, psychological well-being, person-centeredness, access to care, and financial affordability [Today, the results of medico-economic studies are considered to be a tool for authorities whose mission is to inform public decision-making on the allocation of health resources (ex: decisions regarding reimbursement). Currently, the procedure of lobectomy or segmentectomy by VATS is valorised through act GFFA009 . The economic efficiency is not established beyond that time horizon. However, the acceptability curves given will allow decision-makers to judge the probability of efficiency of this technology depending on other WTP thresholds.